Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicyclic pyrazoles

Ranatunge, Ramani R.; Garvey, David S.; Janero, David R.; Letts, L. Gordon; Martino, Allison M.; Murty, Madhavi G.; Richardson, Stewart K.; Young, Delano V.; Zemetseva, Irina S.

doi:10.1016/j.bmc.2004.01.012

Cited by 65 publications

(18 citation statements)

References 23 publications

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“…Constitutive COX-1 which has a housekeeping functions; including gastroprotective and kidney function, regulation of PGs, whereas COX-2 is induced in inflammatory cells and generate PGs that help mediate the inflammatory response. Classical NSAIDs such as aspirin and ibuprofen are non-selective COX inhibitors, which cause a gastric failures like bleeding and ulcer [6,7]. On the other hand, celecoxib, rofecoxib (Vioxx), and valdecoxib are selective COX-2 inhibitors, which exhibit anti-inflammatory and analgesic activity with markedly less gastrointestinal (GI) toxicity.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Screening of Aminoacetylenic Tetrahydrophthalimide Analogues as Novel Cyclooxygenase (Cox) Inhibitors

Basim

Eldeen

Al‐Kaissi

et al. 2017

Int J Pharm Pharm Sci

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Objective: To design and synthesise a new amino acetylenic tetrahydro phthalimide derivative and investigate their selective inhibitory activity to COXs. Methods:Aminoacetylenic tetrahydro phthalimide derivatives were synthesised by alkylation of tetrahydro phthalimide with propargyl bromide afforded 2-(prop-2-yn-1-yl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione. The alkylated tetrahydro phthalimide was subjected to Mannich reaction afforded the desired amino acetylenic tetra phthalimide derivatives (AZ 1-6). The elemental analysis was indicated by the EuroEA elemental analyzer and biological characterization was via IR, 1 H-NMR, 13 C-NMR, DSC was determined with the aid of Bruker FT-IR and Varian 300 MHz spectrometer and DMSO-d6 as a solvent, molecular docking was done using the Autodock Tool software (version 4.2). ChemBioDraw was used in the drawing of our schemes.Results: The IR, 1 H-NMR, 13 C-NMR, DSC and elemental analysis were consistent with the assigned structures. The designers of the compounds as COXs inhibitor activity were based on the nationalisation of the important criteria that provide effective inhibitory binding with COXs-receptor. The results indicated that the synthesised compounds (AZ1-6) showed a close similarity in the binding affinity to both COXs and may be more specific to COX-1. AZ-5 showed the highest % of inhibition for COX-1 even better than aspirin. Which may suggest that the aryl group is required for COX-2 inhibition. Conclusion:For the first time, we indicate the requirement of aromaticity in COX-2 structural inhibitory activity.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Screening of Aminoacetylenic Tetrahydrophthalimide Analogues as Novel Cyclooxygenase (Cox) Inhibitors

Basim

Eldeen

Al‐Kaissi

et al. 2017

Int J Pharm Pharm Sci

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“…COX-2 plays a major role in prostaglandin biosynthesis, inducing inflammatory effects in cells and central nervous system (Habeeb et al, 2001b). Nonsteroidal anti-inflammatory agents (NSAIDs) inhibit the two isozymes to different extents, and this feature accounts for their shared therapeutic properties and side-effects (Ranatunge et al, 2004). The differential tissue distribution of COX-1 and COX-2 has provided a rationale for the development of nonulcerogenic, anti-inflammatory and analgesic, selective COX-2 inhibitors (Soliva et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Lonazolac analogues: molecular modeling, synthesis, and in vivo anti-inflammatory activity

et al. 2009

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A novel series of 1,3-diarylpyrazole derivatives (4-8), analogues to lonazolac, were designed, synthesized, and evaluated for their anti-inflammatory as well as analgesic activities. To target preferential cyclooxygenase-2 (COX-2) inhibitors, the design of these compounds was based upon two different molecular modeling studies. The first study included fit-comparison study of conformational models of compounds 4-8 with a novel validated COX-2 inhibitors hypothesis generated from the corresponding leads I-V using Hip-Hop CATALYST software. The second study included docking study of the designed compounds 4-8 with binding site of COX-1 and COX-2 enzymes using internal coordinate mechanics (ICM)-Pro software. The reported Akaho method was then used to predict the COX-2 preferentiality of the designed compounds. The designed molecules were synthesized and screened for in vivo anti-inflammatory and analgesic activity. Compounds 4a, 6a, and 8b showed high activity in comparison with indomethacin, consistent with virtual molecular modeling studies.

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“…Other reports introduced an atypical central part, such as bicyclic rings (Ranatunge et al, 2004;Beswick et al, 2004;Whitehead et al, 2007), Z-olifens (Jashim Uddin et al, 2004), biphenyls (Chen et al, 2005), and other scaffolds (Kalgutkar and Zhao, 2001). For instance, compound 4, a bicyclic derivative with fused six-membered rings, was found to be a potent COX-2 inhibitor in vitro but it lacked in vivo potency (Joo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Structure-based molecular design, synthesis, and in vivo anti-inflammatory activity of pyridazinone derivatives as nonclassic COX-2 inhibitors

et al. 2009

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Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicyclic pyrazoles

Cited by 65 publications

References 23 publications

Design, Synthesis and Biological Screening of Aminoacetylenic Tetrahydrophthalimide Analogues as Novel Cyclooxygenase (Cox) Inhibitors

Design, Synthesis and Biological Screening of Aminoacetylenic Tetrahydrophthalimide Analogues as Novel Cyclooxygenase (Cox) Inhibitors

Lonazolac analogues: molecular modeling, synthesis, and in vivo anti-inflammatory activity

Structure-based molecular design, synthesis, and in vivo anti-inflammatory activity of pyridazinone derivatives as nonclassic COX-2 inhibitors

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